Methods and apparatus for aerosolizing a substance

ABSTRACT

A device for aerosolizing a liquid includes a chamber having a deformable wall which expands and contracts as fluid is delivered and expelled from a fluid chamber. The chamber is partially bounded by a vibrating structure having holes therein for expelling the fluid. In another aspect, the invention provides exemplary aerosolization apparatus and methods for aerosolizing a substance. A liquid is transferred from a first chamber into a second chamber having a substance that is in a dry state to form a solution. The solution is then transferred from the second chamber and onto an atomization member. The atomization member is operated to aerosolize the solution.

CROSS-REFERENCES TO RELATED APPLICATIONS

[0001] This application is a continuation of U.S. patent applicationSer. No. 09/483,096, filed Jan. 14, 2000, which is a continuation inpart application of U.S. patent application Ser. No. 09/313,914, filedMay 18, 1999, which is a continuation in part of Ser. No. 09/149,426,filed Sep. 8, 1998, which is a continuation in part of Ser. No.09/095,737, filed Jun. 11, 1998, which is a continuation in part of Ser.No. 08/417,311, filed Apr. 5, 1995, the complete disclosures of whichare herein incorporated by reference.

BACKGROUND OF THE INVENTION

[0002] The invention relates generally to the field of inhalation drugtherapy, and in particular to the inhalation of aerosolized chemicalsubstances. In one aspect, the invention provides a portable inhalerhaving a cartridge for storing a chemical substance in a dry state and aliquid dispenser to introduce a liquid to the substance to form asolution. Immediately after formation of the solution, the inhaleraerosolizes the Solution so that it may be administered to a patient.

[0003] The atomization of liquid medicaments is becoming a promising wayto effectively deliver many medicaments to a patient. In particularthere is a potential for pulmonary delivery of protein peptides andother biological entities. Many of these are easily degraded and becomeinactive if kept in a liquid form. Proteins and peptides often exhibitgreater stability in the solid state. This results primarily from twofactors. First, the concentration of water, a reactant in severalprotein degradation pathways, is reduced. See Stability of ProteinPhannaceuticals, M. C. Manning, K. Patel, and R. T. Borchardt, Pharm.Res. 6, 903-918 (1989), the complete disclosure of which is hereinincorporated by reference. Second, the proteins and other excipients areimmobilized in the solid state. Water is a reactant in hydrolysisreactions, including peptide change and cleavage, and deamidation.Reducing the water concentration by freeze-drying or spray drying,reduces this reactant concentration and therefore the rates of thesedegradation pathways.

[0004] The mobility of the peptides or proteins, as well as othermolecules in the formulation, are reduced in the solid or dry state. SeeMolecular Mobility of Amorphous Pharmaceutical Solids Below Their GlassTransition Temperatures, B. C. Hancock, S. L. Shamblin, and G. Zografi,Pharm. Res. 12, 799-806 (1995), the complete disclosure of which isherein incorporated by reference. For the peptides or proteins, thisreduces the rate of intermolecular interactions as well asintramolecular conformational changes or fluctuations in conformation.Minimization of intermolecular interactions will reduce protein andpeptide aggregation/precipitation, and will also reduce the rate ofdiffusion of chemical reactants to the protein or peptide which willslow the rate of chemical degradation pathways. Reduction inintramolecular conformational changes reduces the rate at whichpotentially reactive groups become available for chemical orintermolecular interaction. The rate of this reaction may decrease asthe water concentration, and mobility of the protein, is reduced.

[0005] One way to produce protein in solid or dry state is to transformthe liquid into a fine powder. When used for inhalation delivery, suchpowders should be composed of small particles with a mean mass diameterof 1 to 5 microns, with a tight particle size distribution. However,this requirement increases the processing and packaging cost of the drypowder. See also U.S. Pat. No. 5,654,007 entitled “Methods and Systemfor Processing Dispersible Fine Powders” and U.S. Pat. No. 5,458,135entitled “Methods and Devices for Delivering Aerosolized Medicaments”,the disclosures of which are incorporated herein by reference.

[0006] An easier way to transform a liquid solution to solid or dry formis to use a freeze drying process where a liquid solution is convertedto a solid substance that can be readily reconstituted to a liquidsolution by dissolving it with a liquid, such as water. Hence, oneobject of the present invention is to provide a way to store a solidsubstance and combine the solid substance the with a liquid to form asolution. Once the solution is formed, it is another object of theinvention to rapidly transport the solution to an atomization device toallow the solution to be aerosolized for administration. In this way,the solution is aerosolized immediately after its reconstitution so thatthe degradation rate of the substance is reduced.

[0007] A variety of nebulization devices are available for atomizingliquid solutions. For example, one exemplary atomization apparatus isdescribed in U.S. Pat. No. 5,164,740, issued to Ivri (“the '740patent”), the complete disclosure of which is herein incorporated byreference. The '740 patent describes an apparatus which comprises anultrasonic transducer and an aperture plate attached to the transducer.The aperture plate includes tapered apertures which are employed toproduce small liquid droplets. The transducer vibrates the plate atrelatively high frequencies so that when the liquid is placed in contactwith the rear surface of the aperture plate and the plate is vibrated,liquid droplets will be ejected through the apertures. The apparatusdescribed in the '740 patent has been instrumental in producing smallliquid droplets without the need for placing a fluidic chamber incontact with the aperture plate, as in previously proposed designs.Instead, small volumes of liquid can be placed on the rear surface ofthe aperture plate and held to the rear surface by surface tensionforces.

[0008] A modification of the '740 apparatus is described in U.S. Pat.Nos. 5,586,550 (“the '550 patent”) and 5,758,637 (“the '637 patent”),the complete disclosures of which are herein incorporated by reference.These two references describe a liquid droplet generator which isparticularly useful in producing a high flow of droplets in a narrowsize distribution. As described in the '550 patent, the use of anon-planar aperture plate is advantageous in allowing more of theapertures to eject liquid droplets. Furthermore, the liquid droplets maybe formed within the range from about 1 μm to about 5 μm so that theapparatus will be useful for delivering drugs to the lungs.

[0009] Hence, it is a further objective of the invention to providedevices and methods to facilitate the transfer of liquid solutions(preferably those which have just been reconstituted) to suchaerosolizing apparatus so that the solution may be atomized forinhalation. In so doing, one important consideration that should beaddressed is the delivery of the proper dosage. Hence, it is stillanother object of the invention to ensure that the proper amount ofliquid medicament is transferred to an aerosol generator so that aproper dosage may be delivered to the lungs.

[0010] In still another aspect of the present invention, the presentinvention is directed to methods and devices for delivering fluids to avibrating element

SUMMARY OF THE INVENTION

[0011] The invention provides exemplary systems, apparatus and methodsfor reconstituting a solid phase substance, e.g., a substance that is ina dry state, with liquid to form a solution and for transporting thesolution to an aerosol generator for subsequent atomization. In oneexemplary embodiment, the system comprises a liquid dispenser, acartridge containing a substance in a dry state, and an aerosolgenerator. In use, the cartridge is coupled to an outlet of thedispenser and the dispenser is operated to dispense liquid from theoutlet and into the cartridge. The liquid then flows through thesubstance and exits the cartridge as a solution.

[0012] In an exemplary aspect, the cartridge is replaced and disposedafter each use. After removal of the cartridge the user may optionallyoperate the liquid dispenser to deliver liquid to the aerosol generatorfor a subsequent cleaning cycle. In another exemplary aspect, a liquidoutlet of the cartridge is positioned near the aerosol generator suchthat the solution is dispensed onto the aerosol generator and is readilyavailable for atomization.

[0013] The Liquid Dispenser

[0014] In an exemplary embodiment, the liquid dispenser comprises amechanical pump that is attached to a canister. The liquid dispenser isdisposed within a housing of the inhaler and is configured to deliver apredetermined volume of liquid each time the mechanical pump isoperated. The dispensed liquid then flows directly from the pump to thecartridge to form a solution which in turn is deposited on the aerosolgenerator.

[0015] In one particular aspect, the liquid is a saline solution orsterile water and may optionally contain an anti-microbial additive. Aspreviously mentioned, the solid substance in the cartridge preferablycomprises a chemical that is in the dry state which is reconstitutedinto a solution upon introduction of the liquid from the liquiddispenser.

[0016] In one particularly preferable aspect, the mechanical pumpcomprises a piston pump that is connected to the canister. The pistonpump comprises a spring-loaded piston member that is slidable within acylindrical member which defines a metering chamber. When the pistonmember is moved to a filling position, the metering chamber is filledwith liquid from the canister. When released, the piston member moves toa dispensing position to dispense a known volume of liquid from themetering chamber. In this way, each time the pump is operated, a unitvolume of liquid is dispensed from the piston pump.

[0017] In one particularly preferable aspect, movement of the pistonmember toward the filling position creates a vacuum inside thecylindrical member that gradually increases until the piston memberreaches a point where a passage is provided between the piston memberand the cylindrical member. At this point, the piston member has reachedthe filling position to allow liquid from the canister to be drawn bythe vacuum into the metering chamber of the cylinder. At this point, thepiston member is released and returns by the force of the spring back tothe dispensing position. During the return travel of the piston memberto the dispensing position, the liquid in the metering chamber isdisplaced through an outlet of the pump.

[0018] In another particular aspect, the piston pump is configured todeliver volumes of liquid in the range of about 10 μL to about 50 μLeach time the pump is operated. In another aspect, the piston pump isconfigured such that it will dispense a full unit volume only if theuser fully depresses the piston to the filling position. If the pistonmember is only partially depressed, no liquid will be dispensed. In thismanner, partial dosing is prevented.

[0019] In still yet another aspect, the liquid dispenser furtherincludes a valve which serves to eliminate the dead volume in the pistonpump, thereby inhibiting microbial inflow into the liquid dispenser. Thevalve preferably comprises a tubular valve seat that is slidablydisposed about a distal end of the piston member. In this way, theliquid within the metering chamber moves the tubular valve seat distallyover the piston member to allow the liquid in the metering chamber to bedispensed by flowing between the piston member and the tubular valveseat when the piston member is moved toward the dispensing position. Thetubular valve seat is also slidable within the cylindrical member, andthe cylindrical member defines a stop to stop distal movement of thetubular valve seat relative to the piston member after the unit volumeof liquid has been dispensed from the metering chamber. Further, whenthe spring forces the distal end of the piston member into a distal endof the tubular valve seat, a seal is provided between the piston memberand the tubular valve seat to prevent microbial inflow into the pistonpump. Hence, use of the tubular valve seat in combination with thepiston member and the cylindrical member allows for a unit volume of theliquid within the piston pump to be dispensed and further provides aseal to prevent microbial inflow into the piston pump.

[0020] The Drug Cartridge

[0021] The cartridge of the invention allows for the storage of achemical in a dry state. When a liquid is introduced into the cartridge,the chemical substance dissolves within the liquid to form a solutionjust prior to aerosolization of the solution.

[0022] In one exemplary embodiment, the cartridge comprises a housinghaving an inlet opening and an outlet opening. Disposed in the housingis a chemical substance which is in a dry state. As liquid flows throughthe housing, the substance dissolves and flows through the outletopening as a solution. The chemical substance may be any one of avariety of chemical substances, such as proteins, peptides, smallmolecule chemical entities, genetic materials, and other macromoleculesand small molecules used as pharmaceuticals. One particular substance isa lyophilized protein, such as interferon alpha or alpha 1 prolastin.The lyophilized substance is preferably held in a support structure toincrease the surface area that is in contact with the liquid, therebyincreasing the rate by which the substance is dissolved. The supportstructure is preferably configured to hold the lyophilized substance ina three-dimensional matrix so that the surface area of the substancethat is contact with the liquid is increased. Exemplary types of supportstructures include open cell porous materials having many tortuous flowpaths which enhance mixing so that the solution exiting from the outletend is homogenized. Alternatively, the support structure may beconstructed of a woven synthetic material, a metal screen, a stack ofsolid glass or plastic beads, and the like.

[0023] When used in connection with the aerosolizing apparatus of theinvention, actuation of the liquid dispenser introduces liquid into theinlet opening, through the support structure to dissolve the substance,and out the outlet opening where it is disposed on the aerosol generatoras a solution. The aerosol generator is then operated to aerosolize thesolution. In this way, the substance is stored in a solid state untilready for use. As previously described, the flow of liquid from theliquid dispenser is produced during the return stroke of the pistonmember, i.e. as the piston member travels to the dispensing position.Since the return stroke is controlled by the spring, it is not dependenton the user. In this way, the flow rate is the same each time the liquiddispenser is operated, thereby providing a way to consistently andrepeatedly reconstitute the solution.

[0024] In one particular aspect, the cartridge includes a couplingmechanism at the inlet opening to couple the cartridge to the liquiddispenser. In this way, the cartridge is configured to be removable fromthe liquid dispenser so that it may be removed following each use anddiscarded. In still another aspect, the cartridge is filled with thechemical substance while in a liquid state. The substance is then freezedried and converted to a solid state while in the cartridge.

[0025] The Aerosol Generator

[0026] In an exemplary embodiment, the aerosol generator that isemployed to aerosolize the solution from the cartridge is constructed ina manner similar to that described in U.S. Pat. Nos. 5,586,550 and5,758,637, previously incorporated herein by reference. In brief, theaerosol generator comprises a vibratable member having a front surface,a rear surface, and a plurality of apertures which extend between thetwo surfaces. The apertures are preferably tapered as described in U.S.Pat. No. 5,164,740, previously incorporated herein by reference. In oneparticular aspect, the vibratable member is preferably hemispherical inshape, with the tapered apertures extending from the concave surface tothe convex surface. In use, the solution from the cartridge is suppliedto the rear surface of the vibratable member having the large opening.As the vibratable member is vibrated, the apertures emit the solutionfrom the small openings on the front surface as an aerosolized spray.The user then simply inhales the aerosolized spray to supply thechemical to the patient's lungs.

[0027] Alternative Embodiments

[0028] The invention further provides exemplary methods and apparatusfor aerosolizing a solution. In one exemplary embodiment, an apparatuscomprises a cartridge having a first chamber, a second chamber, and amoveable divider between the first and the second chambers. An exitopening is included in the cartridge and is in communication with thesecond chamber. A liquid is disposed in the first chamber, and asubstance that is in a dry state is in the second chamber. The apparatusfurther includes a piston that is translatable within the cartridge totransfer the liquid from the first chamber and into the second chamberto form a solution. An aerosol generator is further provided and isdisposed near the exit opening to receive the solution from thecartridge and produce an aerosolized solution. In this way, thesubstance may be maintained in a dry state as with other embodimentsuntil ready for aerosolization. To form the solution, the piston ismoved within the cartridge to force the liquid from the first chamberand into the second chamber. Further translation of the piston forcesthe recently formed solution from the second chamber and onto theaerosol generator where the solution is aerosolized.

[0029] In one particular aspect, the divider has a home position where aseal is formed between the divider and the cartridge. In this way, theliquid may be held in the first chamber until the piston is translated.Preferably, the cartridge includes at least one groove that is disposedat least part way between the first and second chambers. In this way, asthe piston is moved within the first chamber, the liquid (which isgenerally incompressible) moves the divider toward the second chamber toallow the liquid to pass around the divider and into the second chamber.The groove preferably terminates at the second chamber so that when thepiston moves the divider into the second chamber, a seal is formedbetween the cartridge and the divider to force the solution from thesecond chamber and out the exit opening.

[0030] In some cases, it may be desirable to draw the solution back intothe first chamber to facilitate mixing. This can be accomplished bywithdrawing the piston back through the first chamber to create a vacuumin the first chamber. To dispense the solution, the piston is translatedback through the first and second chambers as previously described.

[0031] In one particular aspect, a filter is disposed across the exitopening to prevent larger particles from exiting the chamber andclogging the aerosol generator. In another aspect, the apparatusincludes a motor to translate the piston. In this way, an aerosolizedsolution may be supplied to the patient simply by actuating the motor.

[0032] In yet another aspect of the present invention, the presentinvention is also directed to a device for aerosolizing a liquid havinga chamber with a deformable wall. The wall moves between collapsed andexpanded positions to accommodate varying volumes of fluid. The chambermoves to the expanded position in response to fluid being delivered tothe chamber and collapses as fluid is expelled. The chamber contains avolume of 10-1000 μL, more preferably 10-750 μL, and most preferably10-500 μL, while preferably maintaining the fluid pressure of less than15 psi in the chamber. A container, which holds enough liquid to fillthe chamber at least three times, delivers fluid to the chamber. Thewall may be attached to the vibrating structure or may be replaced withthe container.

[0033] The device preferably has a valve positioned between thecontainer and the chamber to isolate the chamber from the container. Thevalve may be formed with the wall so that the valve forms part of thewall. The valve is preferably positioned less than 1 mm from the backside of the vibrating structure so that the chamber has a low volumewhen collapsed. The chamber preferably has a volume of less than 5 μLand more preferably less than 2 μL when collapsed. The valve ispreferably positioned adjacent to the holes in the vibrating structure.

[0034] These and other aspects and advantages of the invention aredescribed in the following description, claims and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

[0035]FIG. 1 illustrates a partial cutaway view of an exemplaryapparatus having an aerosol generator for aerosolizing liquids accordingto the invention.

[0036]FIG. 2 is a schematic diagram of an inhalation flow sensor fordetecting when a patient begins to inhale from an aerosolizing apparatusaccording to the invention.

[0037]FIG. 3 is a cross-sectional side view of an aerosol generator ofthe aerosolizing apparatus of FIG. 1.

[0038] FIGS. 4-9 illustrate cross-sectional side views of a containerand a piston pump used in the apparatus of FIG. 1 to deliver apredetermined volume of liquid to the aerosol generator. The viewsillustrated in FIGS. 4-9 show various states of the piston pump whenmetering and transferring liquids from the container to the aerosolgenerator.

[0039]FIG. 10 is a schematic view of an aerosolizing system having aremovable cartridge holding a substance that is in a solid stateaccording to the invention.

[0040]FIG. 11 illustrates the aerosolizing system of FIG. 10 having thecartridge removed for cleaning of the aerosol generator according to theinvention.

[0041]FIG. 12 is a cross sectional side view of an alternative apparatusfor aerosolizing a solution according to the invention.

[0042]FIG. 13 illustrates a dual chamber drug cartridge and an aerosolgenerator of the apparatus of FIG. 12.

[0043] FIGS. 14-17 illustrate the drug cartridge of FIG. 13 in variousstates of operation to dispense a solution onto the aerosol generatoraccording to the invention.

[0044]FIG. 18 illustrates the apparatus of FIG. 1 with an alternativecartridge to deliver liquids to the aerosol generator according to theinvention.

[0045]FIG. 19 illustrates the cartridge and aerosol generator of FIG.18.

[0046]FIG. 20 is a cross-sectional view of the cartridge of FIG. 19.

[0047]FIG. 21 is a more detailed view of the cartridge of FIG. 19.

[0048]FIG. 22 is a cross-sectional side view of a dispensing systemhaving a drug cartridge and a piston pump according to the invention.

[0049]FIG. 23 shows a chamber having a deformable wall in a collapsedcondition.

[0050]FIG. 24 shows the chamber of FIG. 23 expanded to hold fluid.

[0051]FIG. 25 shows another deformable wall for the chamber.

[0052]FIG. 26 shows the wall of FIG. 25 expanded to hold fluid.

DESCRIPTION OF THE SPECIFIC EMBODIMENTS

[0053] The invention provides exemplary systems, apparatus and methodsfor reconstituting a solid substance that is in a dry state with liquid,such as water, to form a solution and for transporting the solution toan aerosol generator for subsequent atomization. In one exemplaryembodiment, the system comprises a liquid dispenser, a cartridgecontaining the substance that is in the dry state, and an aerosolgenerator. In use, the cartridge is coupled to an outlet of thedispenser. The user then actuates the liquid dispenser so that liquid isdispensed from the dispenser and enters into the cartridge. As theliquid flows through the cartridge, the dry substance is dissolved intothe liquid and exits the cartridge as a solution. Preferably, thecartridge is replaced and disposed after each use. In a preferredembodiment, an outlet end of the cartridge is positioned near theaerosol generator so that the solution disposed on the aerosol generatoris readily available for atomization.

[0054] In one alternative, a two step process is employed toreconstitute the solution and deliver the solution to the aerosolgenerator. First, a portion of a unit volume of liquid, such as one-halfa unit volume, is supplied to the cartridge when the liquid dispenser isoperated. The user then waits a predetermined amount of time, such asabout 10 seconds, and again operates the liquid dispenser to deliversufficient liquid into the cartridge to force a unit volume of solutionfrom the cartridge an onto the aerosol generator. In this way, a periodof time is provided to allow more of the substance to dissolve in theliquid.

[0055] In another aspect of the invention, exemplary systems and methodsare provided for metering relatively small volumes of liquid directlyfrom a container and for delivering the metered volume to an atomizer.The systems and methods are configured to precisely meter and deliverrelatively small volumes of liquid, typically in the range from about 10μL to about 100 μL. When delivering volumes in the range from about 10μL to 50 μL, the invention preferably employs the use of a piston pumpthat is connected to a canister as described in greater detailhereinafter. For volumes in the range from about 50 μL to about 100 μL,a pharmaceutical pump is preferably employed, such as metered dose S4pump, commercially available from Somova S. p.A. Milano, Italy.Optionally, such pharmaceutical pumps may also contain a pharmaceuticalmedicament which may be delivered directly to the aerosol generator. Asone example, the pharmaceutical medicament may comprise a suspension ofcolica steroid for treatment of asthma.

[0056] Another feature of the liquid dispensers of the invention is thatthey are configured to prevent or substantially reduce the possibilityof contamination. In this way, each subsequent dosage delivered by theliquid dispenser is not contaminated when delivered to the atomizer.Referring now to FIG. 1, an exemplary apparatus 10 for atomizing aliquid will be described. Apparatus 10 comprises a housing 12 which isconfigured to hold the various components of apparatus 10. Housing 12 ispreferably constructed to be lightweight and pocket-sized, typicallybeing molded of a plastic material. Housing 12 is divided into twoseparable portions. A first portion 14 includes an electronicscompartment and a second portion 16 includes a liquid holdingcompartment for holding a canister 18, an aerosol generator 22, and amouthpiece 20 through which the atomized liquids are dispensed to thepatient. Conveniently, second portion can be separated from firstportion 14 by sliding a knob 23. Optionally, second portion 16 havingthe liquid holding component may be disposed following separation fromfirst portion 14. Second portion 16 may be disposed along with canister18, or canister 18 may be disposed separately.

[0057] Apparatus 10 further includes an inhalation flow sensor 24 whichdetects the inhalation flow produced by the patient when inhaling frommouthpiece 22. Upon detection of the inhalation, sensor 24 sends anelectrical signal to an electronic circuit (not shown) which in turnsends an alternating voltage to vibrate a piezoelectric member 26 ofaerosol generator 22 to aerosolize a liquid. Sensor 24 preferablycomprises a flexure foil and an electro-optical sensor. The flexiblefoil deflects in response to the inhalation airflow produced when apatient inhales from mouthpiece 20. The optical sensor is configured todetect deflection of the flexible foil so that a signal may be producedto vibrate piezoelectric member 26.

[0058] Referring now to FIG. 2, a schematic diagram of an inhalationflow sensor 24 will be described. Flow sensor 24 comprises a flexiblefoil 28 having an extension 30. Inhalation flow sensor 24 furtherincludes an optical sensor 32 which includes a light emitting diode(LED) 34 and a light sensitive transistor 36 placed in apposition to LED34 so that LED 34 continuously transmits a light beam 38 to transistor36. When the patient inhales, the inhalation airflow causes flexiblefoil 28 to deflect and move extension 30 downward until it crosses lightbeam 38 and causes an optical interruption that is detected bytransistor 36. Transistor 36 then sends a signal to trigger activationof an aerosol generator to produce an aerosol.

[0059] By configuring inhalation flow sensor 24 in this manner, aerosolgenerator 22 is actuated only in response to the detection of aninhalation airflow produced by a patient. In this way, the patient maybe administered a single dose using either a single inhalation ormultiple inhalations. Preferably, inhalation flow sensor 24 is triggeredat an inhalation flow rate of at least 15 liters per minute. However, itwill be appreciated that sensor 24 may be constructed to trigger ateither lower or higher flow rates. Adjustment of the actuation point maybe accomplished by altering the flexible stiffness of foil 28, byselecting different materials for constructing foil 28 or by changingthe thickness of foil 28.

[0060] Alternatively, the inhalation flow sensor may be constructed froma piezoelectric film component. The piezoelectric film componentproduces an electrical signal when it deflects. The magnitude of theelectrical signal is proportional to the magnitude of deflection. Inthis way, the electrical signal that is produced by the piezoelectricfilm component can be used to detect the magnitude of the inhalationflow. In this manner, the output of the aerosol generator may beadjusted in proportion to the inhalation airflow. Such a proportionaloutput from the aerosol generator is particularly advantageous in thatit prevents the coalescence of particles and controls the aerosolproduction according to the inhalation flow. Control of the aerosoloutput may be adjusted by turning the aerosol generator on and offsequentially. The ratio between the on time and the off time, generallydefined as the duty cycle, affects the net flow. An exemplarypiezoelectric film component with such characteristics is commerciallyavailable from ATO Autochem Sensors, Inc., Valley Forge, Pa.

[0061] Referring back to FIG. 1, the electronic circuit (not shown)within first portion 14 includes electrical components to detect thepresence of liquid on aerosol generator 22 and to send a signal to theuser indicating that all of the liquid has been aerosolized. In thisway, the user will know if additional inhalations will be required inorder to receive the prescribed amount of medicament. The sensingcircuit preferably comprises a voltage sensing circuit (not shown) whichdetects the voltage across piezoelectric element member 26. Since thevoltage across piezoelectric member 26 is proportionally related to theamount of liquid in surface tension contact with an aperture plate 40(see FIG. 3) of aerosol generator 22, it can be determined, based on thevoltage, whether any liquid is left remaining. For example, whenaerosolization is initiated, the voltage is high. At the end ofaerosolization, the voltage is low, thereby indicating that theaerosolization process is near completion. Preferably, the sensingcircuit is configured to be triggered when about 95% of the liquid hasbeen aerosolized. When triggered, the sensing circuit turns on a lightemitting diode (LED) 42 indicating that the prescribed dosage has beendelivered.

[0062] Referring now to FIG. 3, construction of aerosol generator 22will be described in greater detail. As previously described, aerosolgenerator 22 includes a vibratable aperture plate 40 and annularpiezoelectric member 26. Aerosol generator 22 further comprises acup-shaped member 44 to which piezoelectric member 26 and aperture plate40 are attached as shown. Cup-shaped member 44 includes a circular hole46 over which aperture plate 40 is disposed. Wires (not shown) connectpiezoelectric member 26 to the electrical circuitry within portion 14(see FIG. 1) which in turn is employed to vibrate piezoelectric member26.

[0063] Cup-shaped member 44 is preferably constructed of a low dampingmetal, such as aluminum. Aperture plate 40 is disposed over hole 46 suchthat a rear surface 48 of aperture plate 40 is disposed to receiveliquid from canister 18 (see FIG. 1). Although not shown, aperture plate40 includes a plurality of tapered apertures which taper from rearsurface 48 to a front surface 50. Exemplary aperture plates which may beused with the invention include those described the '740 patent, the'550 patent, and the '637 patent, previously incorporated by reference.

[0064] Aperture plate 40 is preferably constructed of a material thatmay be produced by a metal electroforming process. As an example,aperture plate 40 may be electroformed from palladium or a palladiumalloy, such as palladium cobalt or palladium nickel. Aperture plate 40may further be gold electroplated to enhance its corrosion resistance.Alternatively, aperture plate 40 may be constructed of nickel, anickel-gold alloy, or a combination of nickel and nickel-gold alloyarranged such that the nickel-gold alloy covers the external surfaces ofthe aperture plate. The nickel-gold alloy may be formed using a goldelectroplating process followed by diffusion at an elevated temperatureas described generally in Van Den Belt, TGM, “The diffusion of platinumand gold in nickel measured by Rutherford Fact Scattering Spectrometry”,Thin Solid Film, 109 (1983), pp. 1-10. The complete disclosure of thisreference is incorporated herein by reference. A small amount ofmanganese may also be introduced to the nickel during the electroformingprocess so that the nickel can be heat treated at an elevatedtemperature as described generally in U.S. Pat. No. 4,108,740,incorporated herein by reference. The gold-nickel alloy is particularlyuseful in protecting the nickel components, and particularly theelectroformed nickel components, from corrosion caused by platingporosity. The diffusion process may be useful for other applicationswhich require corrosion protection for nickel components, andparticularly nickel electroformed components, such as, for example,inkjet aperture plates, other spray nozzle plates, and the like.

[0065] As another alternative, corrosion resistance of the apertureplate may be enhanced by constructing the aperture plate of a compositeelectroformed structure having two layers, with the first electroformedlayer comprising nickel and the second electroformed layer comprisinggold. The thickness of the gold in the composite in preferably at leasttwo microns, and more preferably, at least five microns. Alternatively,the second layer may be electroformed from palladium or anothercorrosive-resistant metal. The external surfaces of the aperture platemay also be coated with a material that prevents bacteria growth, suchas polymyxin or silver. Optionally, other coatings that enhancewetability may be applied to the aperture plate.

[0066] In one embodiment, the aperture plate is protected from corrosiveliquids by coating the aperture plate with agents that form a covalentbond with the solid surface via a chemical linking moiety. Such agentsare preferred because the are typically biocompatable with acidicpharmaceutical liquids. The agent may be photoreactive, i.e. activatedwhen subjected to light or may be activated when subjected to moistureor to any other means of energy. Further, the agent may have varioussurface properties, e.g. hydrophobic, hydrophilic, electricallyconductive or non-conductive. Still further, more than one agent may beformed on top of each other. Types of coatings that may be included onthe aperture plate are described in U.S. Pat. Nos. 4,979,959; 4,722,906;4,826,759; 4,973,493; 5,002,582; 5,073,484; 5,217,492; 5,258,041;5,263,992; 5,414,075; 5,512,329; 5,714,360; 5,512,474; 5,563,056;5,637,460; 5,654,460; 5,654,162; 5,707,818; 5,714,551; and 5,744,515.The complete disclosures of all these patents are herein incorporated byreference.

[0067] Cup-shaped member 44 is disposed within a housing 52 whichprevents liquids from coming into contact with piezoelectric member 26and with cup-shaped member 44. Cup-shaped member 44 is suspended withinhousing 52 by two elastic rings 54 and 56. Ring 54 is positioned betweenhousing 52 and the circumference of cup-shaped member 44. Ring 56 ispositioned between the inner diameter of piezoelectric member 26 and ashield member 58. Such an arrangement provides a hermetic seal thatprevents the contact of liquids with the piezoelectric member 26 withoutsuppressing the vibratory motion of cup-shaped member 44.

[0068] Referring back now to FIG. 1, aerosol generator 22 is axiallyaligned with mouthpiece 20 so that when piezoelectric member 26 isvibrated, liquid droplets are ejected through mouthpiece 20 and areavailable for inhalation by the patient. As previously described,disposed within second portion 16 is a canister 18 which holds theliquid medicament to be atomized by aerosol generator 22. Canister 18 isintegrally attached to a mechanical pump 60 which is configured todispense a unit volume of liquid through a nozzle 62 to aerosolgenerator 22. Pump 60 is actuated by pressing a knob 64 which pushescanister 18 downward to generate the pumping action as described ingreater detail hereinafter. Pressing on knob 64 also puts pressure on anelectrical microswitch 66 within second portion 16. When actuated,microswitch 66 sends a signal to the electrical circuit within firstportion 14 causing a light emitting diode (LED) (not shown) to blinkindicating that apparatus 10 is ready for use. When the patient beginsto inhale, the inhalation is sensed causing actuation of the aerosolgenerator.

[0069] As illustrated in FIG. 3, pump 60 delivers a unit volume ofliquid 68 (shown in phantom line) to rear surface 48 of aperture plate40. The delivered volume 68 adheres to aperture plate 40 by solid/liquidsurface interaction and by surface tension forces until patientinhalation is sensed. At that point, piezoelectric member 26 is actuatedto eject liquid droplets from front surface 50 where they are inhaled bythe patient. By providing the delivered volume 60 in a unit volumeamount, a precise dose of liquid medicament may be atomized anddelivered to the lungs of the patient. Although canister 18 of FIG. 1 isshown as being configured to directly deliver the dispensed liquid tothe aperture plate, pump 60 may alternatively be configured to receive acartridge containing a chemical in a dry state as described in greaterdetail hereinafter.

[0070] Referring now to FIGS. 4-10, a schematic representation of acanister 138 and a piston pump 140 will be described to illustrate anexemplary method for dispensing a unit volume of a liquid medicament toan aperture plate, such as aperture plate 40 of apparatus 10 (see FIGS.1 and 3). Canister 138 comprises a housing 142 having an open end 144about which a cap 146 is placed. Disposed against open end 144 is awasher 148 which provides a seal to prevent liquids from escaping fromhousing 142. On top of washer 148 is a cylindrical member 150. Cap 146securely holds cylindrical member 150 and washer 148 to housing 142.Cylindrical member 150 includes a cylindrical opening 151 which allowsliquids to enter from canister 138. Cylindrical member 150 incombination with washer 148 also serve to securely position a holdingmember 152 about which a compression spring 154 is disposed.

[0071] Piston pump 140 comprises a piston member 156, cylindrical member150, a valve seat 158 and compression spring 154. Piston member 156 hasa frontal end 156A and a distal end 156B, with frontal end 156Aproviding the piston action and distal end 156B providing the valveaction.

[0072] Piston pump 140 is configured such that every time valve seat 158is depressed toward canister 138 and then released, a unit volume ofliquid is dispensed through a tapered opening 161 in valve seat 158.Valve seat 158 includes a valve seat shoulder 158A which is pressed tomove valve seat inwardly, causing valve seat 158 to engage with distalend 156B to close tapered opening 161.

[0073] As shown in FIG. 5, as piston member 156 is further depressedinto cylindrical member 150, spring 154 is compressed and a meteringchamber 168 begins to form between frontal end 156A and cylindricalmember 150. Frontal end 156A and distal end 156B are preferablyconstructed from a soft elastic material which provides a hermetic sealwith cylindrical member 150 and valve seat 158, respectively. Due to theseal between frontal end 156A and cylindrical member 150, a vacuum iscreated within metering chamber 168 upon depression of piston member156.

[0074] As piston member 156 is further moved into cylindrical member 150(see FIG. 6), spring 154 is further compressed and frontal end 156Amoves past cylindrical opening 151 so that a gap is provided betweenfrontal end 156A and cylindrical member 150. As frontal end 156A passesthe edge of cylindrical member 150, liquid from canister 138 is drawninto cylindrical member 150 by the vacuum that was created withinmetering chamber 168. In FIG. 6, piston member 156 is in the fillingposition.

[0075] At the end of inward travel, the user releases the pressure onvalve seat 158, allowing spring 154 to push piston member 156 backtoward its starting position. As illustrated in FIG. 7, upon the returntravel of piston member 156 to the starting position, frontal end 156Aagain engages cylindrical member 150 and forms a seal between the twosurfaces to prevent any liquid within metering chamber 168 from flowingback into canister 138.

[0076] Since the liquid within metering chamber 168 is generallyincompressible, as spring 154 pushes on piston member 156, the liquidwithin metering chamber 168 forces valve seat 158 to slide distally overpiston member 156. In so doing, the liquid within metering chamber 168is allowed to escape from the metering chamber through tapered opening161 of valve seat 158 as illustrated in FIG. 8.

[0077] As illustrated in FIGS. 7-9, liquid from metering chamber 168 isdispensed from tapered opening 161 as frontal end 156A travels length L.As frontal end 156A passes through length L, it is in contact withcylindrical member 150. In this way, the liquid within metering chamber168 is forced out of tapered opening 161 during this length of travel.After passing through Length L, frontal end 156A passes out of sealingrelationship with cylindrical member 150 so that no further liquid isdispensed from tapered opening 161. Hence, the amount of liquiddispensed is proportional to the diameter of cylindrical member 150 overlength L. As such, piston pump 140 may be designed to dispense a knownvolume of liquid each time piston member 156 travels from the startingposition to the filling position and then back to the starting position.Since piston member 156 must be fully depressed to the filling positionin order to create a gap between frontal end 156A and cylindrical member150, a way is provided to ensure that partial volumes can not bedispensed.

[0078] As shown in FIG. 9, valve seat 158 includes a shoulder 170 whichengages a stop 172 on cylindrical member 150 to stop distal movement ofvalve seat 158 relative to cylindrical member 150. At this point, pistonpump 140 is at an ending dispensing position which corresponds to thestarting position as initially illustrated in FIG. 4. In this position,spring 154 forces distal end 156B of piston member 156 into taperedopening 161 to provide a seal and prevent contaminants from enteringinto piston 140.

[0079] Valve seat 158 is preferably coated with a material that inhibitsproliferation of bacteria. Such coatings can include, for example,coatings having a positive electric charge, such as polymyxin,polyethylinimin, silver, or the like.

[0080] The invention further provides a convenient way to store chemicalsubstances in the solid or dry state and then to dissolve the chemicalsubstance with liquid from the canister to form a solution. In this way,chemical substances that are otherwise susceptible to degradation can bestored in the dry state so that the shelf life of the product isextended. An exemplary embodiment of a cartridge 180 for storing suchchemical substances that are in the dry state is illustrated in FIG. 10.For convenience of illustration, cartridge 180 will be described inconnection with piston pump 140 and canister 138, which in turn may becoupled to an aerosolization apparatus, such as apparatus 10, toaerosolize a medicament as previously described. Cartridge 180 comprisesa cylindrical container 182 having an inlet opening 184 and outletopening 186. Inlet opening 182 is sized to be coupled to piston pump 140as shown. Disposed within container 182 is a first filter 188 and asecond filter 190. Filter 188 is disposed near inlet opening 184 andsecond filter 190 is disposed near outlet opening 186. A chemicalsubstance 192 which is in a dry state is disposed between filters 188and 190. Chemical substance 192 is preferably held within a supportstructure to increase the rate in which the chemical substance isdissolved.

[0081] The support structure may be constructed of a variety ofmaterials which are provided to increase the rate in which the chemicalsubstance is dissolved. For example, the support structure may comprisean open cell material such as a polytetrafluoroethylene (PTFE) matrixmaterial commercially available from Porex Technologies, Farburn, Ga.Preferably, such an open cell material has a pore size in the range fromabout 7 μm to about 500 μm, and more preferably about 250 μm.Alternatively, various other plastic materials may be used to constructthe open cell matrix, including olyethylene (HDPE), ultra-high molecularweight polyethylene (UHMW), polypropylene (PP), polyvinylidene fluoride(PVDF), nylon 6 (N6), polyethersulfone (PES), ethyl vinyl acetate (EVA),and the like. Alternatively, the support structure may be constructed ofa woven synthetic material, a metal screen, a stack of solid glass orplastic beads, and the like.

[0082] An exemplary method for placing chemical substance 192 intocontainer 182 is by filling container 182 with the chemical substancewhile the chemical substance is in a liquid state and then lyophilizingthe substance to a dry state while the substance within the cartridge.In this way, filling of cartridge 180 with a chemical substance may beprecisely and repeatedly controlled. However, it will be appreciatedthat the chemical substance may be placed into cartridge 180 when in thesolid state.

[0083] Lyophilization is one exemplary process because it will tend toreduce the rate of various physical and chemical degradation pathways.If the substance comprises a protein or peptide, both the lyophilizationcycle (and resulting moisture content) and product formulation can beoptimized during product development to stabilize the protein beforefreezing, drying and for long term storage. See Freeze Drying ofProteins, M. J. Pikal, BioPharm. 3, 18-26 (1990); Moisture InducedAggregation of Lyophilized Proteins in the Solid State, W. R. Liu, R.Langer, A. M. Klibanov, Biotech. Bioeng. 37, 177-184 (1991); FreezeDrying of Proteins. II, M. J. Pikal, BioPharm. 3, 26-30 (1990);Dehydration Induced Conformational Transitions in Proteins and TheirInhibition by Stabilizers, S. J. Prestrelski, N. Tedeschi, S. Arakawa,and J. F. Carpenter, Biophys. J. 65, 661-671 (1993); and Separation ofFreezing and Drying Induced Denaturation of Lyophilized Proteins UsingStress-Specific Stabilization, J. F. Carpenter, S. J. Prestrelski, andT. Arakawa, Arch. Biochem. Biphys. 303, 456-464 (1993), the completedisclosures of which are herein incorporated by reference. Adjustment ofthe formulation pH and/or addition of a wide variety of additivesincluding sugars, polysaccharides, polyoles, amino-acids, methylamines,certain salts, as well as other additives, have been shown to stabilizeprotein towards lyophilization.

[0084] As an example, which is not meant to be limiting, a cartridge waspacked with small glass beads having a diameter of approximately 0.5 mm.The cartridge was filed with a solution of lysozyme at a concentrationof 10 mg/ml. To enhance its stability, the solution was combined with aform of sugar and with a buffer solution. The buffer solution was sodiumcitrate, and the sugar was mannitol. A twin 20 surfactant was also addedto the solution. The solution was then lyophilized in the cartridge.

[0085] The lyophilized substance may optionally contain a solubilityenhancer, such as a surfactant as described in Journal of PharmaceuticalScience Technology which is J.Pharmsei. Technology, 48; 30-37 (1994) thedisclosure of which is herein incorporated by reference. To assist inprotecting the chemical substance from destructive reactions while inthe dry state, various sugars may be added as described in Crowe, etal., “Stabilization of Dry Phospholipid Bilayer and Proteins by Sugars”,Bichem. J. 242: 1-10 (1987), and Carpenter, et al. “Stabilization ofPhosphofructokinase with Sugars Drying Freeze-Drying”, Biochemica. etBiophysica Acta 923: 109-115 (1987), the disclosures of which are hereinincorporated by reference.

[0086] In use, cartridge 180 is coupled to piston pump 140 and pistonpump 140 is operated as previously described to dispense a known volumeof liquid into cartridge 180. The supplied liquid flows through chemicalsubstance 192 and chemical substance 192 dissolves into the liquid andflows out of outlet opening 186 as a liquid solution 194. Outlet opening186 is spaced apart from an aperture plate 196 of an aerosol generator198 so that liquid solution 198 will be deposited on aperture plate 196as shown. Aerosol generator 198 further includes a cup shaped number 200and a piezoelectric member 202 and operates in a manner similar to theaerosol generator 22 as previously described. Hence, when aerosolgenerator 198 is operated, liquid solution 194 is ejected from apertureplate 196 in droplet form as shown.

[0087] One important feature of the invention is that cartridge 180 isremovable from piston pump 140 so that cartridge 180 may be discardedfollowing each use. As illustrated in FIG. 11, after cartridge 180 hasbeen removed, the user may optionally actuate piston pump 140 to againdeliver a volume of liquid 204 directly to aperture plate 96. Aerosolgenerator 198 is then operated so that, similar to an ultrasoniccleaner, the vibratory action removes any residual solution fromaperture plate 196. Liquids that may be held within canister 138 to formthe solution and to clean aperture plate 196 include sterile water, amixture of water with ethanol or other disinfectant, and the like.

[0088] In summary, the invention provides a portable aerosolizingapparatus that is able to store a chemical substance in the dry state,and to reconstitute the chemical substance with liquid to form asolution just prior to administration. The invention further providestechniques for aerosolizing the solution and for cleaning the aerosolgenerator. Also, it will be appreciated that the aerosolizationapparatus as described herein may be used to aerosolize a liquidmedicament that is not stored within a cartridge so that the liquidmedicament is passed directly from the piston pump and on to theaperture plate for aerosolization.

[0089] Apparatus 10 may optionally be configured to warn the user whencleaning is needed. Such a feature is best accomplished by providing aprocessor within second portion 14 which is programmed to include anexpected amount of time required to aerosolize a dose received fromcanister 18. If the expected amount of time exceeded before the entiredose is aerosolized, it may be assumed that the apertures in theaperture plate are clogged, thereby requiring cleaning to clear theapertures. In such an event, the processor sends a signal to an LED onapparatus 10 indicating that cleaning is needed.

[0090] To determine whether all of the liquid has been aerosolized inthe expected time period, the processor records the amount of time thatthe aerosol generator is actuated. When the aerosol generator has beenactuated for the expected time, the voltage sensing circuit is actuatedto detect whether any liquid remains on the aperture plate as previouslydescribed.

[0091] Referring now to FIG. 12, an alternative embodiment of anapparatus 300 for atomizing a liquid solution will be described.Apparatus 300 includes a housing 302 that is divided into two separableportions similar to the embodiment of FIG. 1. A first portion 304includes various electronics and a second portion 306 includes a liquidholding compartment. An aerosol generator 308 which is similar toaerosol generator 22 of FIG. 1 is disposed in second portion 306 toaerosolize a solution where it will be available for inhalation througha mouthpiece 310. Conveniently, aerosol generator 308 includes a lip 312to catch the solution and maintain it in contact with the aerosolgenerator 308 until aerosolized. Disposed above aerosol generator 308 isa drug cartridge 314. As will be described in greater detailhereinafter, cartridge 314 is employed to produce a solution which isdelivered to aerosol generator 308 for aerosolization.

[0092] Coupled to cartridge 314 is a lead screw 316. In turn, lead screw316 is coupled to a micro-coreless DC motor 318. When motor 318 isactuated, it causes a shaft 320 to rotate. This rotational motion isconverted to linear motion by lead screw 316 to translate a piston 322within cartridge 314 as described in greater detail hereinafter. Motor318 is actuated by appropriate electronics held in first portion 304.Further, a power source, such as a battery, is also held within firstportion 304 to supply power to motor 318. Aerosol generator 38 isoperated in a manner essentially identical to that previously describedin connection with the apparatus of FIG. 1.

[0093] Referring now to FIG. 13, construction of cartridge 314 will bedescribed in greater detail. Piston 322 includes a docking knob 324which mates with a connector 326 of lead screw 316. Docking knob 324 andconnector 326 are configured to facilitate easy coupling and uncoupling.Typically, motor 318 and lead screw 316 are securely coupled to housing308 (see FIG. 12), while cartridge 314 is configured to be removablefrom housing 302. In this way, each time a new drug cartridge isrequired, it may be easily inserted into apparatus 300 and coupled withlead screw 316.

[0094] Lead screw 316 is configured such that when motor 318 causesshaft 320 to rotate in a clockwise direction, lead screw 316 is moveddownward. Alternatively, when motor 318 is reversed, lead screw 316 ismoved upward. In this way, piston 322 may be translated back and forthwithin cartridge 314. Motor 318 is preferably calibrated such thatpiston 322 can be moved to selected positions within cartridge 314 asdescribed in greater detail hereinafter.

[0095] Cartridge 314 includes a first chamber 328 and a second chamber330. Although not shown for convenience of illustration, first chamber328 is filled with a liquid and second chamber 330 includes a substancethat is in a dry state. Such a substance preferably comprises alyophilized drug, although other substances may be employed similar tothe embodiment of FIG. 1. Separating first chamber 328 and secondchamber 330 is a divider 332. As shown in FIG. 13, divider 332 is in ahome position which forms a seal between divider 332 and cartridge 314so that the liquid is maintained within first chamber 328 until divider332 is moved from its home position as described hereinafter.

[0096] Cartridge 314 includes an exit opening 333 which is disposed inclose proximity to aerosol generator 308. Once the solution is formedwithin cartridge 314, it is dispensed through exit opening 333 and on toaerosol generator 308 where it will be aerosolized for delivery to thepatient. Disposed across exit opening 333 is a filter 334 which servesto prevent larger drug particles from being flushed out onto aerosolgenerator 308, thus causing potential clogging of the apertures withinaerosol generator 308.

[0097] Referring now to FIGS. 14-17, operation of cartridge 314 toproduce a solution which is delivered to aerosol generator 308 will bedescribed. Cartridge 314 is constructed in a manner similar to the drugcartridge described in U.S. Pat. No. 4,226,236, the complete disclosureof which is herein incorporated by reference. As shown in FIG. 14,cartridge 314 is in the home position where divider 332 maintains theliquid within first chamber 328. When in the home position, cartridge314 may be inserted into apparatus 300 and coupled to lead screw 316(see FIG. 13). When ready to deliver an aerosolized solution to apatient, motor 318 (see FIG. 13) is actuated to cause lead screw 316 totranslate piston 322 within cartridge 314 as illustrated in FIG. 15. Aspiston 322 is translated within cartridge 314, it begins to move throughfirst chamber 328. Since the liquid is generally incompressible, theliquid will force divider 332 to move in the direction of second chamber330. Formed in the walls of cartridge 314 are one or more grooves 336which are placed in communication with first chamber 328 as divider 332moves away from its home position. As such, the liquid within firstchamber 328 is forced into chamber 330 as illustrated by the arrows.Once the liquid is able to flow around divider 332, the pressure actingagainst it is relieved so that it remains in the position generallyshown in FIG. 15. As the liquid enters into second chamber 330, thelyophilized drug is dissolved into the liquid to form a solution.

[0098] As illustrated in FIG. 16, piston 322 is translated until itengages divider 332. At this point, all of the liquid has beentransferred from first chamber 328 into second chamber 330. At thispoint, it may optionally be desired to mix the solution that has justbeen formed within second chamber 330. This may be accomplished bytranslating piston 322 backward toward the position illustrated in FIG.15. In so doing, a vacuum is created within first chamber 328 to drawthe solution from second chamber 330 into first chamber 328. As thesolution flows through grooves 336, the solution is agitated, causingmixing. Piston 322 may then be translated back to the position shown inFIG. 16 to move the liquid back into second chamber 330. This processmay be repeated as many times as needed until sufficient mixing hasoccurred.

[0099] After proper mixing, the solution is ready to be dispensed ontothe aerosol generator. To do so, piston 332 is moved through secondchamber 330 as illustrated in FIG. 17. In turn, divider 332 is pushedagainst filter 334 to completely close second chamber 330 and force allof the liquid out exit opening 333.

[0100] One particular advantage of cartridge 314 is that a precisevolume of drug is dispensed onto aerosol generator 308 to ensure thatthe patient will receive the proper dosage. Further, by maintaining thedrug in the dry state, the shelf life may be increased as previouslydescribed.

[0101] Following dispensing of the solution, cartridge 314 may beremoved and replaced with another replacement drug cartridge.Optionally, a cleaning cartridge may be inserted into apparatus 300which includes a cleaning solution. This cleaning solution is dispensedonto aerosol generator 308 upon operation of motor 318. Aerosolgenerator 308 may then be operated to clean its apertures using thecleaning solution.

[0102] Referring now to FIG. 18, an alternative apparatus 400 foratomizing a liquid will be described. Apparatus 400 is essentiallyidentical to apparatus 10 except that canister 18 has been replaced witha continuous feed cartridge 402. Cartridge 402 is configured tocontinuously feed liquid to aerosol generator 22 on demand so thatenough liquid will always be available each time aerosol generator 22 isactuated. Cartridge 402 also ensures that excessive liquid will not besupplied, i.e. it will supply only as much liquid as is atomized.Cartridge 402 is constructed similar to the cartridges described inco-pending U.S. patent application Ser. No. 08/471,311, filed Apr. 5,1995, the complete disclosure of which is herein incorporated byreference.

[0103] As illustrated in FIGS. 19-21, cartridge 402 comprises a liquidreservoir 404 and a face 406 which is adjacent the aperture plate ofaerosol generator 22 to supply liquid from liquid reservoir 404 to theaperture plate. A capillary pathway 408 extends between reservoir 404and face 406 to supply liquid to face 406 by capillary action. In orderto overcome the vacuum that is produced in reservoir 404, a ventingchannel 410 is in communication with pathway 408. In this way, air isable to enter into reservoir 404 to reduce the vacuum and allowadditional liquid to be transferred from reservoir 404.

[0104] In another embodiment, a drug cartridge may be coupled to apiston pump to form a dispensing system that is used to supply aformation to an aerosol generator. For example, as shown in FIG. 22, adispensing system 430 comprises a cartridge 432 and a piston pump 434.Cartridge 432 is patterned after cartridge 314 of FIG. 14 and includes afirst chamber 436 and a second chamber 438. Disposed in chamber 436 is aliquid (not shown) and disposed in second chamber 438 is a driedsubstance 440. A divider 442 separates the chambers. In use, a plunger444 is moved through chamber 436 to force divider 442 forward and toallow the liquid to enter chamber 438 and form a solution.

[0105] Piston pump 434 may be constructed similar to pump 138 of FIG. 4.Pump 434 is operated to dispense a volume of the solution from chamber438. Pump 434 may be disposed near an aerosol generator so that a volumeof the solution will be available for atomization. In this way, knownvolumes of a solution that was formed from a direct substance may beprovided in an easy and convenient manner.

[0106] Referring to FIGS. 23 and 24, another aspect of the invention isshown wherein the same or similar reference numbers refer to the same orsimilar structure. A container 500 delivers fluid to a chamber 502. Thecontainer 500 and chamber 502 are contained within the housing 12(FIG. 1) and the aspects of the devices described above are equallyapplicable here. Fluid from the container 500 fills the chamber 502 atleast three times and more preferably at least twenty five times.

[0107] The chamber 502 is movable between the expanded position of FIG.24 to the collapsed position of FIG. 23. The chamber 502 expands asfluid is delivered to the chamber 502 from the container 500 andcollapses as fluid is expelled through holes 504 in a vibratingstructure 506 during operation. The holes 504, which are exaggerated forclarity, are preferably shaped and sized in the manner described herein.The vibrating structure 506 is formed by the cup shaped member 44 and anelement 508 having the holes 504. The element 508 has a domed shape butmay be flat, curved or shaped in any other suitable manner. Thevibrating structure 506 preferably vibrates at a frequency of 80-190kHz, more preferably about 120-150 kHz, but may also operate at otherfrequencies. The vibrating structure 506 is vibrated with any suitabledevice and is preferably vibrated with the piezoelectric member 26.

[0108] The chamber 502 has a deformable wall 510 which deforms tocontain varying amounts of fluid. The wall 510 preferably bows outwardand away from the vibrating structure 506 when the chamber 502 expands(FIG. 24). The chamber 502 is also bounded by a back side 503 of theelement 508 so that fluid in the chamber 502 is in contact with thevibrating structure 506. The chamber 502 preferably contains a volume of10-1000 μL, more preferably 10-750 μL and most preferably about 10-500μL when fully expanded. The wall 510 may be somewhat elastic, however,the wall 510 is preferably flexible enough that the fluid pressure inthe chamber 502 is no more than 15 psi, more preferably no more than 10psi, and most preferably no more than 5 psi when the chamber 502 isfull. Fluid tension developed at the holes 504 in the vibratingstructure hold the fluid within the chamber 502.

[0109] The container 500 has a piston 512 movable within a cylinder 514containing the fluid. The piston 512 moves within the cylinder 514 todeliver a known quantity of fluid to the chamber 502. The piston 512 maybe manually actuated or moved with a motor-driven actuator. Thecontainer 500 may, of course, be any other suitable device or container500 including any other device described herein, without departing fromthe scope of the invention. Thus, the container 500 may have a number ofcompartments containing different substances and may have the valvesdescribed above.

[0110] A cap 516 is mounted to the container 500. The cap 516 has aneedle 518 which pierces a septum 520 on the container 500. The cap 516is preferably attached to the container 500 immediately before use sothat the septum 520 is not pierced until just before the container 500is mounted within the housing 12. The container 500 is then mounted to aholding element 522 with a threaded connection 524. The holding element522 is mounted within the housing 22 in any suitable manner. The needle518 defines a fluid path 526 between the container 500 and the chamber502.

[0111] A valve 528 maintains sterility in the container 500 and preventsfluid flow from the chamber 502 to the container 500. The valve 528 ispreferably a slit-type valve 530 but may, of course, have any othersuitable structure. The valve 528 has upper and lower lips 532, 534which connect the valve 528 to the wall 510. The valve 528 may also havea threaded connection with the wall 510 which engages the wall 510 asthe container 500 engages the holding element 522.

[0112] Use of the device is now described. The cap 516 is attached tothe container 500 so that the needle 518 pierces the septum 520.Alternatively, the cap 516 may be already attached to the container 500with the valve 528 maintaining sterility of the container 500 beforeuse. The cap 516 is then rotated into engagement with the holdingelement 522 which causes the valve 528 to engage and the wall 510. Theuser then selects a desired amount of fluid to be delivered to thechamber 502. The piston 512 is then moved an appropriate distance todeliver the desired amount of fluid. As fluid is delivered from thecontainer 500, the valve 528 opens and the chamber 502 expands toaccommodate the fluid. The chamber 502 may be completely or partiallyfilled. As the chamber 502 is filled, the fluid pressure preferablyremains within the ranges described above. The piezoelectric member 26is then used to induce vibrations in the vibrating structure 506.Vibration of the vibrating structure 506 forces fluid from the chamber502 through the holes 504 and out front side 507 of the vibratingstructure 506.

[0113] Referring to FIGS. 25 and 26, another aspect of the invention isshown wherein the same or similar reference numbers refer to the same orsimilar structure. The dimensions, operation and use described above,such as in connection with FIGS. 23 and 24, are equally applicable here.The container 500 and chamber 502 operate similar to the container 500and chamber 502 described above in that the container 500 delivers fluidto the chamber 502. The chamber 502 is partially defined by the backside 503 of the vibrating structure 506 and a deformable wall 510A.

[0114] The container 500 differs from the container 500 in that wall510A may be replaced periodically and, in the preferred embodiment, isreplaced with each new container 500. A cap 516A has the needle 518 forpenetrating the septum 520 on the container 500 as described above. Thecap 516A, needle 518, and wall 510A may be mounted to the container 500immediately before mounting the container 500 to the holding element522. Alternatively, the wall 510A, needle 518, cap 516A and container500 may be packaged together. A valve 530, preferably a slit-type valve532, is formed at the end of the needle 518 to isolate the chamber 502from the container 500. The valve 530 defines a fluid outlet 534positioned less than 1 mm and more preferably less than 0.5 mm from theback side 503 of the vibrating structure 506. The valve 530 ispreferably positioned adjacent the holes 504 in the vibrating structure506.

[0115] A spring 534 holds the wall 510A against the vibrating structure506 to seal the chamber 502. The spring 534 is compressed as thecontainer 500 is advanced into engagement with the holding element 522.The spring 534 is embedded in the wall 510A and in the cap 516A. Thewall 510A is preferably made of a material that has a low bendingstiffness which produces little resistance when expanding. In thismanner, the pressure in the chamber may still be less than 15 psi andmore preferably less than 10 psi as mentioned above. The fluid pressuresare maintained at the fluid volumes mentioned above.

[0116] The wall 510A has a portion 536 which conforms to the shape ofthe back side 503 of the vibrating structure 522 when collapsed so thatthe fluid can be substantially, and preferably completely, removed fromthe chamber 502. In this manner, the volume remaining in the chamber 502is less than 10 μL, more preferably less than 5 μL and most preferablyless than 2 μL. The portion 536 of the wall 510A conforming to thevibrating structure 522 is preferably adjacent the holes 504 in thevibrating structure 506.

[0117] In another aspect of the invention, the vibrating structure 506is able to drop the pressure in the chamber 502 below atmosphericpressure to help collapse the wall 510, 510A. When the vibratingstructure 522 is vibrated, fluid can be forced through the holes 504when pressure in the chamber 502 is below atmospheric pressure. Thedevice shown in FIGS. 25-26 is used in the same manner as the device ofFIGS. 23-24 and the discussion above is incorporated here.

[0118] The invention has now been described in detail, however, it willappreciated that certain changes and modifications may be made. Forexample, although illustrated in the context of delivering liquid to anaperture plate, the apparatus and methods may be employed to deliverknown quantities of liquid to other types of atomization devices.Therefore, the scope and content of this invention are not limited bythe foregoing description. Rather the scope and content are to bedefined by the following claims.

What is claimed is:
 1. A device for aerosolizing a liquid, comprising: ahousing; a vibrating structure having a front side, a back side and aplurality of holes extending between the front and back sides, thevibrating structure being mounted within the housing; means forvibrating the vibrating structure; a container containing a fluid andmounted within the housing; a chamber having a deformable wall movablebetween a collapsed position and an expanded position, the chamber beingpartially defined by the back side of the vibrating element, the chamberreceiving fluid from the container for delivery through the plurality ofholes in the vibrating element upon vibration with the vibrating means.2. The device of claim 1, wherein: the chamber moves to the expandedposition in response to fluid being delivered to the chamber and movesto the collapsed position as fluid is expelled through the plurality ofholes.
 3. The device of claim 1, wherein: the chamber contains a volumeof 10-1000 μL in the expanded condition.
 4. The device of claim 1,wherein: the chamber contains a volume of less than 10 μL when in thecollapsed condition.
 5. The device of claim 1, further comprising: avalve positioned between the container and the chamber, the valvepreventing flow from the chamber to the container.
 6. The device ofclaim 5, wherein: the valve encloses part of the chamber.
 7. The deviceof claim 6, wherein: the valve is removably mounted to the housing andis replaced together with the container.
 8. The device of claim 1,wherein: the vibrating means is a piezoelectric element coupled to thevibrating structure.
 9. The device of claim 1, further comprising: afluid outlet positioned to deliver fluid from the container to thechamber, the fluid outlet being positioned no more than 1 mm from theback side of the vibrating structure.
 10. The device of claim 1,wherein: the chamber contains the fluid at a fluid pressure of less than15 psi when in the expanded position.
 11. The device of claim 1,wherein: the chamber contains the fluid at a fluid pressure of less than5 psi when in the expanded position.
 12. The device of claim 1, wherein:the container has a piston movable within a fluid cylinder containingthe fluid, the piston being movable within the cylinder to deliver aknown quantity of fluid to the chamber.
 13. The device of claim 1,wherein: the container is removably mounted to the housing forreplacement with another container.
 14. The device of claim 1, wherein:the wall is attached to the container and is replaced when the containeris replaced.
 15. The device of claim 1, wherein: the wall has a portionwhich generally conforms to a shape of the back side of the vibratingstructure when in the collapsed position.
 16. The device of claim 1,wherein: the wall bows outward and away from the vibrating structurewhen moving from the collapsed position to the expanded position. 17.The device of claim 1, wherein: the wall is mounted to the vibratingstructure.
 18. The device of claim 1, wherein: the vibrating structurevibrates at a frequency of 120-150 kHz.
 19. A method of aerosolizing aliquid, comprising the steps of: providing a device for aerosolizing aliquid, the device having a housing, a vibrating structure, a container,and a chamber, the vibrating structure having a plurality of holestherein extending between a front side and a back side, the containercontaining a fluid and having a fluid outlet through which fluid isexpelled into the fluid chamber, the container being mounted within thehousing, the chamber being at least partially defined by a wall and theback side of the vibrating structure; delivering a desired quantity offluid to the fluid chamber; and vibrating the vibrating element to expelthe desired quantity of fluid from the fluid chamber.
 20. The method ofclaim 19, wherein: the delivering step is carried out with the chambermoving toward the expanded position; and the vibrating step expels fluidwhich causes the wall to move toward the collapsed position.
 21. Themethod of claim 19, wherein: the providing step is carried out with thechamber having a volume of 10-1000 μL in the expanded condition.
 22. Themethod of claim 19, wherein: the providing step is carried out with avalve positioned between the container and the chamber, the valvepreventing flow from the chamber to the container.
 23. The method ofclaim 19, further comprising the step of: removing and replacing thevalve and the container with another valve and container.
 24. The methodof claim 19, wherein: the delivering step is carried out with a fluidpressure of less than 15 psi in the chamber.
 25. The method of claim 19,further comprising the step of: removing and replacing the wall.
 26. Themethod of claim 25, wherein: the removing and replacing step is carriedout by also removing and replacing the container.
 27. The method ofclaim 19, wherein: the providing step is carried out with a springurging the wall against the vibrating structure to seal the wall. 28.The method of claim 19, wherein: the providing step is carried out withthe wall attached to the container.
 29. The method of claim 19, wherein:the providing step is carried out with the wall having a portion whichgenerally conforms to a shape of the back side of the vibratingstructure when in the collapsed position.
 30. The method of claim 19,wherein: the providing step is carried out with the wall mounted to thevibrating structure.
 31. The method of claim 19, wherein: the vibratingstep is carried out with the pressure in the chamber being less than apressure at the front side of the vibrating structure.
 32. A method foraerosolizing a substance, the method comprising: transferring a liquidfrom a first chamber into a second chamber having a substance in a drystate to form a solution; transferring the solution from the secondchamber onto an atomization member; and operating the atomization memberto aerosolize the solution.
 33. An aerosolizing apparatus, comprising: acartridge having a first chamber, a second chamber, a movable dividerbetween the first and the second chambers, and an exit opening incommunication with the second chamber, wherein a liquid is disposed inthe first chamber and a substance that is in a dry state is in thesecond chamber; a piston translatable within the cartridge to transferthe liquid from the first chamber and into the second chamber to form asolution; and an aerosol generator disposed near the exit opening toreceive the solution from the cartridge and produce an aerosolizedsolution.